Eosinophils are cells of the innate immunity. They are produced in the bone marrow and preferably circulate in the blood. The main effector function of eosinophils is an immediate release of cytoplasmic granules in response to activation by various stimuli. Cytoplasmic granules comprise pro-inflammatory mediators: cytokines, chemokines, lipid- and neuromediators, growth factors, and cationic proteins. The cationic proteins of eosinophils include 4 classes: major basic protein (MBP), eosinophil peroxidase (EPO), eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN). In combination, these proteins have a cytotoxic action on both infectious microorganisms and tissues of a host, causing eosinophilic inflammation [Hogan S P, Rosenberg H F, Moqbel R, et al. Eosinophils: biological properties and role in health and disease//Clin Exp Allergy. 2008; 38(5):709-50].
The eosinophil count in the blood is normally 0.02-0.3 109/L, or 0.5 to 5% of the total leukocytes. An increased blood eosinophil count relative to the normal level is eosinophilia. Hypereosinophilia or large eosinophilia is a condition when the content of eosinophils in the blood is 15% or more, usually when the total leukocyte count is increased [Hoffman R, Benz Jr. E J, Shattil S J, et al., eds. Hematology: Basic Principles and Practice. 4th ed. Philadelphia, Pa.: Churchill Livingston; 2005:768].
An increased level of eosinophils in the blood and tissues accompanies diseases of various etiology and pathogenesis. They include parasitic invasions, a broad spectrum of allergic diseases, such as asthma, rhinitis, nasal polyps, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, and atopic dermatitis; rheumatic diseases (rheumatoid arthritis, diffuse eosinophilic fasciitis, Churg-Strauss syndrome, nodular periarteritis); and pathologies of unclear etiology (eosinophilic esophagitis, eosinophilic gastroenteritis) [Blanchard C, Rothenberg M E. Biology of the eosinophil//Adv Immunol. 2009; 101:81-121].
Among allergic diseases, bronchial asthma, which is a chronic inflammatory airway disease that is characterized by episodic airflow obstruction, inflammation of the respiratory tract, and by an increased bronchial reactivity to non-specific allergens, is medically most important.
There are a lot of evidences that eosinophils are a key component of an allergic response in asthma. IL-3 and IL-5 secreted by mast cells provide the accumulation of eosinophils in lungs, followed by activation of these cells, which is accompanied by the release of LTC4, eosinophil cationic protein, major basic protein, neurotoxin, eosinophil peroxidase (EPO), transforming growth factor, and free radicals [Blanchard C, Rothenberg M E. Biology of the eosinophil//Adv Immunol. 2009; 101:81-121].
The activity of the inflammatory process in asthma has been found to be in direct correlation with the serum level of eosinophil cationic protein [Bjornsson E., Janson C., Hakansson L. et al. Serum eosinophil cationic protein in relation to bronchial asthma in young Swedish population. Allergy 1994; Vol. 49: 400-407]. Lavage fluid of patients with bronchial asthma has an increased eosinophil count. The eosinophil cell surface has low-affinity receptors for IgE and due to that eosinophils may be directly activated by cause-significant allergens. The eosinophil cell surface has further been found to have receptors for IL-2, IL-3, IL-5, GM-CSF, PAF, and prostaglandins. Through these receptors, the above-mentioned cytokines and lipid mediators are able to induce the activation of eosinphils that release mediators (LTC4, PAF) and cytokines (IL-3, IL-4, IL-5, IL-8, GM-CSF, TGFβ). Destruction of the airway epithelium, which results from the action of eosinophil proteins, causes the development of bronchial hyperreactivity and a reduction in the barrier function of the airway epithelium.
Now, a great attention is being attached to the role of eosinophils in the regeneration and remodulation of tissues because of a clear relationship that have been found to exist between eosinophilia in tissues and some fibrous diseases (endomyocardial fibrosis complicated with hepatic fibrosis in patients with hypereosinophilic syndrome, nodular sclerosing Hodgkin's disease, and subepithelial fibrosis in bronchial asthma) [Noguchi H. et al. Tissue eosinophilia and eosinophil degranulation in syndromes associated with fibrosis//Am. J. Pathol. 1992, Vol. 140. P. 521-528].
Eosinophils are a source of a number of fibrogenic and growth factors, including transforming growth factor-β (TGF-β) fibroblast growth factor (FGF)-2, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-9, IL-1β, IL-13, and IL-17. Clinical trials involving anti-IL-5 antibodies also supported the role of eosinophils in the events associated with the deposition of specific matrix proteins in the reticular basement membrane [Kay A B, Phipps S, Robinson D S. A role for eosinophils in airway remodeling in asthma//Trends Immunol. 2004, Vol. 25, P. 477-82].
Today, the most common method for treating asthma is the use of corticosteroids (budesonide, beclomethasone dipropionate, fluticasone propionate, mometasone furoate) by inhalation. However, corticosteroids function by inducing a general immunosuppressive action, and there are adverse side effects caused by long-term administration thereof, such as high blood pressure, osteoporosis, and cataract development [Barnes P J. New drugs for asthma//Semin Respir Crit Care Med. 2012; 33(6):685-94]. Corticosteroids should be administered every day, and patient's compliance with this requirement is therefore another problem for the successful use of said therapeutic agents. In addition, there are corticosteroid-insensitive patients who need an alternative therapy. Selective targeting to eosinophils may overcome the side effects caused by the use of systemic immunosuppressive agents with pleiotropic action.
The drugs for reducing eosinophilia by inhibiting the interaction between interleukin-5 and receptor IL-5Rα on the eosinophil cell surface are currently in clinical trials. Such drugs include humanized monoclonal anti-IL-5 antibodies (mAt) and concurrent IL-5Rα inhibitors.
Among IL-5 neutralizing monoclonal antibodies, SB240563 (mepolizumab, Glaxo Smith Kline) is most effective. There are reports [Nair P, Pizzichini M M M, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. NEJM. 2009; 360:985-93] that mepolizumab therapy of patients with prednisolone-dependent asthma reduces eosinophilia in the blood and sputum and, most importantly, improves patient's quality by reducing exacerbation frequency and a prednisolone dose. Another clinical trial showed that the administration of anti-IL-5 antibodies (mepolizumab) to the patients with corticosteroid-insensitive asthma also led to a reduction in exacerbation frequency and improved patient's quality according to the AQLQ (Asthma Quality of Life Questionnaire). In addition to the action on asthma, this trial also showed a therapeutic effect against polypous rhinosinusopathy [Haldar P, Brightling C E, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. NEJM. 2009; 360:973-84].
In an independent clinical trial in adults with polypous rhinosinusopathy, mepolizumab significantly reduced the levels of ECP and a soluble form of IL-5Rα in the blood, and the concentration of IL-5Rα, IL-6, and IL-1b in the nose, which correlated with an alleviation of the disease, according to the total polyp score [Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol. 2011; 128(5):989-995].
The use of anti-IL-5 antibodies is not limited to bronchial asthma and polypous rhinosinusopathy. This therapy is also effective in other eosinophil-mediated diseases. For example, in patients with hypereosinophilic syndrome, mepolizumab therapy reduced eosinophilia in the blood and made it possible to reduce the administered dose of prednisolone [Rothenberg M E, Klion A D, Roufosse F E, et al. Treatment of patients with the hypereeosinophilic syndrome with mepolizumab. NEJM. 2008; 358(12):1215-28]. Patients with eosinophilic esophagitis treated with anti-IL-5 antibodies showed an improved clinical picture associated with a reduced dysphagia and a six-fold reduction in the blood eosinophil count, and in some patients, esophageal epithelial hyperplasia was reduced [Stein M L, Collins M H, Villanueva J M, et al. Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis. J Allergy Clin Immunol. 2006; 118(6):1312-9]. Clinical trials of the drug in children showed that the patients having in the blood not more than 20 eosinophils in one field of microscope had improved symptoms, such as redness, fragility, and grooves and vertical lines on the esophageal mucosa [Assa'ad A H, Gupta S K, Collins M H, et al. An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis. Gastroenterology. 2011; 141(5):1593-604].
Mepolizumab is also successfully used as therapy of eosinophilic vasculitis [Kahn J E, Grandpeix-Guyodo C, Marroun I, et al. Sustained response to mepolizumab in refractory Churg-Strauss syndrome. J Allergy Clin Immunol. 2010; 125:267-70]. In a 28-aged female, monthly administration of mepolizumab reduced the blood eosinophil count to normal, prevented the formation of corticosteroid asthma, and based on x-ray data, improved the condition of the lung parenchyma [Kim S, Marigowda G, Oren E, Israel E, Wechsler M. Mepolizumab as a steroid-sparing treatment option in patients with Churg-Strauss syndrome. J Allergy Clin Immunol. 2010; 125:1336-43]. In clinical trials in patients with eosinophilic vasculitis and pronounced eosinophilia, mepolizumab therapy made it possible to reduce the dose of corticosteroids. Eosinophilia also reduced, but after the trial completion, the exacerbation was repeated [Oldhoff J M, Darsow U, Werfel T, et al. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy. 2005; 60(5):693-6].
Mepolizumab is reported [Amini-Vaughan Z J, Martinez-Moczygemba M, Huston D P. Therapeutic strategies for harnessing human eosinophils in allergic inflammation, hypereosinophilic disorders, and cancer//Curr Allergy Asthma Rep. 2012, Vol. 12, No. 5. P. 402-412] hat to be in the second phase of clinical trials of therapy for asthma, eosinophilic esophagitis in adults, eosinophilic esophagitis in children, eosinophilic vasculitis, and polypous rhinosinusopathies, and in the third phase of clinical trials as a treatment of hypereosinophilic syndrome, eosinophilic esophagitis in children, rhinovirus-induced asthma, and chronic obstructive bronchitis. Another medicament, reslizumab (Cephalon), which is also a humanized monoclonal anti IL-5 antibody SCH55700, is in the second phase of clinical trials as a therapy for hypereosinophilic syndrome and loiasis, and in the third phase as a therapy of asthma and eosinophilic esophagitis in children. All these allow for concluding that selective therapy aimed at reducing eosinophilia is a perspective approach to the treatment of diseases mediated by this cell type (bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, polypous rhinosinusopathy, eosinophilic esophagitis, eosinophilic vasculitis, and hypereosinophilic syndrome).
However, mAt therapy has several drawbacks. Monoclonal antibodies are expensive therapeutic agents that should be administered for a month or two. An important factor is a problem of patient's non-compliance with physician's order, which is because of multiple visits to a physician's office to receive the drug injections. In addition, allotype divergence between a patient and a therapeutic antibody can lead to that the monoclonal antibody-based therapy becomes ineffective. A high dose of mAt and a possibility of forming immune complexes also may reduce the efficiency of passive immunization.
Other methods providing therapeutic agents against pathological conditions characterized by eosinophilia are disclosed in WO 97/45448 and WO 03/040164. Application WO 97/45448 provides the use of “modified and variant forms of IL5 molecules capable of antagonizing or reducing, in another way, the activity of IL-5” to improve, alleviate, or reduce effects deviated from the norm, which are caused by native and mutant forms of IL5. It is reported that the antagonizing action is a result of variant forms of IL5 that bind with the low-affinity chain of IL5R but not with high-affinity receptors. Acting in such a way, the variants compete with IL5 for binding with its receptors without any effect on the physiological action of IL5.
Application WO 03/040164 provides a composition for vaccination directed to endogenous formation of antibodies to IL-5, IL-13, and eotoxin, i.e. to key factors of maturation, activation, localization, and vitality of eosinophils. The composition comprises a virus-like particle and at least one protein or peptide of IL-5, IL-13 and/or eotaxin bound thereto. According to the invention, said composition is useful in the production of vaccines for the treatment of allergic diseases with an eosinophilic component and as a pharmaccine to prevent or cure allergic diseases with an eosinophilic component.
Application No. 8501176 provides the use of antibodies binding to IL-5R. These antibodies comprise a binding site recognizing IL-5 receptors (IL-5R) and Fc-fragment. The claimed method reduces the eosinophil count in the blood, marrowbone, gastro-intestinal tract (for example, esophagus, stomach, small intestine and large gut), or lungs, thereby reducing clinical manifestations of asthma and chronic obstructive bronchitis of lungs in human beings (http://www.patentgenius.com/patent/8501176.html).
Yong Sup Lee et al. in Studies on the site-selective N-acyliminium ion cyclazation: synthesis of (±)-glochidine and (±)-glochidicine, Heterocycles, Vol 37, No 1. 1994, disclose the preparation of histamine succinimide by fusing histamine dihydrochloride together with succinic anhydride under heating the initial reagents to 200-230° C. for 40 minutes.
The publication of international application WO 2007/007054 discloses succinimide and glutarimide derivatives of general formula (I), having inhibitory action on DNA methylation in cells, in particular tumor cells. Compounds disclosed in said publication are prepared by an addition reaction between an amino derivative comprising a hydrocarbon chain and a corresponding anhydride or acid, or ester, followed by optional cyclization, if necessary in the presence of a base.
The described methods of synthesis imides of glutaric acid comprise heating a dicarboxylic acid or a derivative thereof, such as anhydride, diester, etc., with a primary amine or amide thereof (thermal cyclization) [Weigand-Hilgetag, Eksperimentalnye metody v organicheskoi khimii [Experimental Methods in Organic Chemistry], ed. by N. N. Suvorov, M., Khimiya, 1968; p. 446], cyclization of monoamides of corresponding dicarboxylic acids by using a dehydrating agent as a carboxylic group-activating reagent, such as acetic anhydride [Shimotori et al, Asymmetric synthesis of 5-lactones with lipase catalyst. Flavour and Fragrance Journal, 2007, V. 22, No. 6, P. 531-539], acetyl chloride [Ito et al., Chemoselective Hydrogenation of Imides Catalyzed by CpRu(PN) Complexes and Its Application to the Asymmetric Synthesis of Paroxetine.//Journal of the American Chemical Society, 2007, V. 129, No. 2, P. 290-291], carbonyldiimidazole [Polniaszek, et al., Stereoselective nucleophilic additions to the carbon-nitrogen double bond. 3. Chiral acyliminium ions.//Journal of Organic Chemistry, 1990, V. 55, No. 1, P. 215-223], glutaric or succinic anhydrides [Ainhoa Ardeo et al, A practical approach to the fused β-carboline system. Asymmetric synthesis of indolo[2,3-α]indolizidinones via a diastereoselective intramolecular α-amidoalkylation reaction./Tetrahedron Letters, 2003, 44, 8445-8448].
The international publication of patent application WO2007/000246 provides a method of synthesis of glutarimides by alkylation of piperidine-2,6-dione and pyrrolidin-2,5-dione with corresponding halo derivatives in DMF, followed by separating the target substituted imide derivatives by preparative chromatography, which is not applicable for the synthesis of macro amounts.
Thus, the object of the present invention is the use of non-toxic glutarimide derivatives effective for the treatment of eosinophilic diseases, preferably of allergic nature, such as bronchial asthma, allergic rhinitis, polypous rhinosinusopathies, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, Churg-Strauss syndrome, anaphylactic shock, Quincke's edema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis, and fibroses.